We have developed a novel radiopeptide therapy using the somatostatin analog, 111-In-pentetreotide, to treat malignancies that have a high level of expression of somatostatin receptors. This targeted biologic approach offers several advantages: somatostatin receptors are found in high density in many tumors, 111-In-pentetreotide binds with high affinity to its receptor and is internalized into the cancer cell, 111-In-pentetreotide is minimally immunogenic, and compared to larger, bulkier antibodies, there is better tumor penetration despite an unfavorable hydrostatic gradient. We treated 39 patients with 111-In-pentetreotide and observed therapeutic activity and minimal toxicity. In cloning assays, we established that the combination of 111-In-pentetreotide and camptothecin are additive/synergistic. Camptothecin binds topoisomerase I, stabilize the topoisomerase I:DNA complex as a protein-linked DNA break (PLDB) and produce double strand (ds) DNA breaks that lead to apoptosis. Our research group has established a unique cell model and used this model to characterize several specific mechanisms of resistance to camptothecin. In this proposal, we will conduct a clinical trial to determine the optimal dose of the camptothecin analog, irinotecan, that can be given with 111-In-pentetreotide. We will correlate the pharmacokinetics of the radioisotope and dosimetry with clinical toxicity and response. We will obtain serial biopsies and fully characterize the expression of somatostatin receptors in the tumors of the patients treated in this study. In cell lines that express somatostatin receptors, we will study mechanisms of resistance to radioisotope therapy and to camptothecin. These preclinical studies will identify potentially important mechanisms of in vivo resistance that will be analyzed in the tumor biopsies taken from patients in this study and subequent studies of 111-In-pentetreotide therapy. These translational studies will serve as the basis for expanding a novel therapeutic modality for neuroendocrine cancers.